Early-stage reduction of the dendritic complexity in basolateral amygdala of a transgenic mouse model of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, and the pathogenesis of AD has always been a popular issue in modern neuroscience research [1]. AD can be characterized by loss of memory and cognitive defects in behavioral pathology, which have been the focus of several studies regarding the mechanism and treatment of AD [2]. Although extracellular depositions of amyloid-beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) can be found in some AD patients and animal models, clinical trials have failed to give an effective treatment to prevent, halt, or reverse AD [3]. A number of studies indicate that early intervention treatment, before the onset of cognitive symptoms, would be more effective, but the clinical onset time of AD and the mechanism underlying the changes in neuronal circuits is not clearly known [4].
Some subcortical regions are affected by deposits with the progressive development of AD in patients and transgenic animal models [5], [6]. As the main brain area controlling emotional activities and associative memories, the basolateral amygdaloid nucleus (BLA) is significantly affected showing considerable shrinkage, distortion, loss of neurons and neuronal morphological alterations [7], [8]. These dendritic abnormalities as key hallmarks in the early stages of the AD, adumbrate neuroanatomical degeneration, including dystrophic neurites, reduction of dendritic complexity and loss of dendritic spines [9].
APPswe/PS1dE9 (hereinafter, APP/PS1) double-transgenic mice express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both involved in neurons of the central nervous system [10]. Previous reports revealed that plaque depositions were found in the brains of the transgenic mice starting at 6 months old, while there was a reduction in the dendritic complexity of BLA at 12–14 months old [6], [11], [12]. However, the mouse model of AD displays cognitive and memory deficits at 3–8 months old [13]. The morphological integrity of neurons identifying the amygdaloid circuits was not clear with respect to the progressive changes in early stages of AD.
To address the neural changes on a large-scale, during the early pathological development of AD, we used the APP/PS1 double-transgenic mice as AD models. By combining Golgi-Cox staining with Micro-Optical Sectioning Tomography (MOST), we acquired the reconstructed projection neurons in the BLA at developmental stages of AD and examined their dendritic morphology [14], [15]. The results showed that the progressive Aβ depositions and reduction of dendritic complexity could be identified in 6- and 9-month-old mice.
Section snippets
Animals
APP/PS1 mice were used as Alzheimer's disease models, and C57BL/6J mice were used as controls, with a 12-h light/dark cycle (8:00 a.m. to 8:00 p.m.), in stable conditions of temperature (22 °C) and humidity (60%), with food and water ad libitum. Only male mice at the corresponding ages of 6 and 9 months were used in this study. Five mice were used in each group for immunohistochemistry/Nissl staining, and 2 mice were used in each group for whole-brain imaging. All protocols and procedures were
Amyloid plaques and neuron density in developing APP/PS1 mice
We first investigated the pathological changes in developing AD mice. Following immunohistochemistry (Fig. 1a–c) and Nissl staining (Fig. 1d–f), we extracted image blocks from 6-month-old and 9-month-old APP/PS1 mice (hereinafter referred to as AD_6M and AD_9M for reconstruction group, respectively), and 6-month-old C57BL/6J mice (hereinafter referred to as CON for reconstruction group). To obtain quantitative data on plaque levels, microscopic images of anti-Aβ antibody-stained brain slices
Discussion
In this study, the reconstructed projection neurons in the BLA, at different ages of the APP/PS1 transgenic model, were analyzed for pathological changes in dendritic arbor and compared to the changes in C57BL/6J mice. The results showed that the following: (1) at the neuron-level, the AD_9M group had significantly fewer branches compared to the CON group, while there was no significant difference in total branch number and length between the AD_6M and CON groups; (2) at the branch-level,
Conflict of interest
We declare that we have no conflict of interest for this manuscript.
Acknowledgements
We thank Dr. Tonghui Xu and all members of MOST group for help in experiments and comments on manuscript writing. We also thank the Optical Bioimaging Core Facility of WNLO-HUST for the support in data acquisition.
This work is supported by National Natural Science Foundation of China (No. 81171067), Science Fund for Creative Research Group of China (No. 61421064), the Natural Science Foundation of Hubei Province (No. 2015CFB448) and Director Fund of WNLO. The funders had no role in study
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